Polyvinylpyrrolidone penicillin treatment of bovine mastitis



United States Patent 2,968,592 POLYVINY-L-PYRROLIDONE PENICILLINTREATMENT OF BOVINE MASTITIS Clifton Robert Curtis, Hamiiton, NY,assignoljto Hamilton Pharmacal Company, Inc, Hamilton, N.Y.

NoDrawing. Filed Ma s, 1957, SerrNo. 657,735 8 Claims. or. 167-531 Thisinvention :relates to the treatment of bovine mastitis and to a novelcomposition :for the treatment of bovine mastitis by sintramammaryinjection.

Polyvinylpyrrolidone, generally referred to as PVP, has in recent yearsbeen employed for various .purposes in the fields of pharmaceuticals andcosmetics. Originally resulting as a product of the study ofacetylenechemistry, polyvinylpyrrolidone had its first use during WorldWar II as a blood plasma extender or expander and as a blood plasmasubstitute.

Polyvinylpyrrolidone is a white, amorphous powder which is soluble inwater as w'ellas ina Wide variety of organic solvents. In addition toits use "as a plasma extender or substitute, polyvinylpyrrolidone hasbeen variously proposed and to some extent used to retard the absorptionof various drugs, including penicillin and insulin; to reduce toxicityand irritating properties of various chemical substances,no'tably'iodineyand as a "solubilizing agent.

Studies of the eifect of polyvinylpyrrolidone on phar macologic activityhave led researchers and writers -on the subject to the conclusion thatthe 'etfectof this material is quite unpredictable, even when appliedwithin a group of related compounds like the barbiturates. Theconclusion is that the effect of polyvinylpyrrolidone is specific ratherthan general and that its action in connection with individualsubstances or individual pharmacologic uses must'be closely studied ineach individual case, even when the individual uses are closely *relatedchemically. Polyvinylpyrrolidone forms chemical complexes with varioussubstances and does not form complexes in solution with other apparentlyrelated substances.

- The treatment of bovine mastitis up to now has been chiefly byintramammary injection'of antibiotics, :notably penicillin anddihydrostreptomycin. -I have found :that remarkable rates of cure areachieved by using combinations of antibiotics and polyvinylpyrrolidone.The outstanding results achieved cannot be due to the usual and expectedinfluences of polyvinylpyrrolidone, such as merely prolonging the actionof the antibiotics or by re duction in toxicity or irritation.

Speaking generally, in cases of bovine mastitis and udder infection, theintramammary administration of antibiotics produces cures in a generalaverage of less than eighty percent of cases whereas the treatment withantibiotics plus polyvinylpyrrolidone produces cures in nearly onehundred percent of the cases.

In one example of treatment in accordance with the method of the presentinvention the dosage comprised 20 cc. of vehicle emulsion containing1,000,000 units of penicillin, 1 gram of dihydrostreptomycin and 1 gramof poly-vinylpyrrolidone. The amount of vehicle employed inadministering a given dosage of active ingredients is not at allcritical and may vary widely. In the bovine administration ofantibiotics some veterinarians prefer to use relatively large quantitiesof vehicle in greatly enlarged udders 'to promote dissemination of theantibiotic material.

The vehicles used in treatment according to the present invention arethose generally .used in penicillin administration, namely mineral oilor mineral oil emulsion or vegetable oil plus suspending agents. Anexample is Plastibase which is marketed by E. R. Squibb & Sons. I-LP.vehicle of the Hamilton Pharmacal Company comprises mineral oil emulsioncontaining cholesterol emulsifiers. .Bristol Laboratories, Inc. providea patented vehicle comprising aluminum monostearate in either peanut,sesame or mineral oils.

The above dosage was administered to both dry and lactating cows. Dryquarters received only one treatment and lactating quarters received twotreatments. In this particular test run .19 of the infected cows werelactatingand 5 were dry. Two months after initial treat ment four of thefive dry cows tested entirely negative (cured) and seventeen of thenineteen lactating cows tested entirely negative.

Surveys made under the New York State Mastitis Control Program over a.period of the last ten years indicate that, in the foregoing group of24 cows, there would be from 6 to 7 post treatment infections followingtreatment by 'antibotics al'one,without polyvinylpyrrolidone.

Another test and .survey of a herd of 12 cows, '11 lactating and 1 dry,showed no positive quarters whatever after treatment .in the manner setout in the first example. :Inthis herd the normal experience followingtreatment with antibiotics alone would have been 3 or 4 positive posttreatment infections.

The foregoing tests were made throughthe College of Veterinary Medicineof Cornell University, at Ithaca, New York, by field veterinarians ofthe New York State Mas'titis ControlProgram. 'Theconclusion of theparticipating veterinarians was that the results were very remarkableandcould not have beenattained without polyvinylpyrrolidone.

In tests conducted by a team-of veterinarians in Turlock, California,similar results were noted, using varying dosages of antibiotics andpolyvinylpyrrolidone. These tests involved the treatment of severalhundred infected quarters with polyvinylpyrrolidone.

In one instance of a fresh first calf heifer the right rear-quarter wasextremely hard and swollen with very little secretion. The affectedquarter was infused every 12 hours with 1,000,000 units of penicillin, 1gram .of dihydrostreptomycin, and 21 :gram of polyvinylpyrrolidone incc. .of sterile water. This quarter returned to normal in 4 to 5 days.The veterinarians making these tests state that heretofore dozens ofsimilarly infected quarters in first calf heifers have been treated withantibiotics alone without avail, the quarter being destroyed before itbegan to produce.

In another instance of a four year old cow fresh, with two mastitisquarters, each quarter was treated with 1,000,000 units of penicillinand 1 gram of dihydrostreptomycin in 250 cc. of water. In one of thequarters 1 gram of polyvinylpyrrolidone was added to the dosage and thisquarter responded much more quickly than the other.

In a further instance a cow with the left front quarter badly swollenand the right rear quarter only moderately swollen was treated. Bothquarters received the same antibiotic treatment but the badly swollenquarter re ceived, in addition, one gram of polyvinylpyrrolidone twicedaily. Both quarters returned to normal in the same length of time.

In a further series of tests at Turlock, California, fourteen cows,including Holsteins, Guernseys and Jerseys, in which each cow had aboutthe same degree of mastitis in two or more quarters, were treated. Allof the quarters were given one million units of penicillin and one gramof dihydrostreptomycin in 250 cc. of sterile Water, with smallerrepeated doses daily for three days. In addition, half the quarters wereinjected with one gram of polyvinylpyrrolidone twice daily during thetreating period. Without exception the quarters receiving the additionalpolyvinylpyrrolidone treatment responded more quickly and morecompletely.

In another herd of 125 milking Holsteins, a dozen mastitis cows weretreated as above with half of the infected quarters treated withantibiotics alone and half with the same antibiotic treatment pluspolyvinylpyrrolidone. The latter quarters came back to milk quicker thanthe ones receiving antibiotics alone and it was observed that of all ofthe polyvinylpyrrolidone treated quarters none remained swollen.

Extensive tests indicate that polyvinylpyrrolidone possessesanti-inflammatory properties when infused into the bovine udder, whichproperties result in opening of the ducts and better drainage of clots.Polyvinylpyrrolidone appears to act synergistically with antibiotics toreduce swelling and congestion quickly and in a manner which cannot beachieved by antibiotics alone, no matter. how the latter may beadministered as to amount or frequency of dosage or the particularantibiotics employed.

In testing and practicing the present invention polyvinylpyrrolidone hasbeen combined and used successfully with procaine penicillin G,crystalline potassium penicillin G, dihydrostreptomycin, neomycin andpolymyxin B.

Severe and acute inflammatory reaction to infections normally produceafter-damage to udder tissues. This after-damage is greatly reduced asthe result of the polyvinylpyrrolidone treatment and in most cases noclinical after-damage was found upon examination two weeks aftertreatment. When polyvinylpyrrolidone is used in conjunction withantibiotics in bovine mastitis and udder infection there is a morecomplete recovery in swollen quarters and these quarters are left withless permanent scar tissue than when antibiotics are used alone.Polyvinylpyrrolidone is especially effective in treating the very acutehot cases of mastitis where this is extreme hardness, pain and swelling.

In other tests dosages including 500,000 units of penicillin with 1 gramof polyvinylpyrrolidone have been employed successfully and lesseramounts of penicillin, in some cases as low as 100,000 units, may beemployed when the question of residual penicillin in the milk isconsidered to be objectionable.

In tests which were otherwise the same as those specified above twograms of polyvinylpyrrolidone were employed instead of one withsubstantially the same result. Furthermore, in certain of the tests only250 mg. of dihydrostreptomycin was used instead of 1 gram, with goodresult.

I claim:

1. The treatment of bovine mastitis and udder infection which comprisesperiodic intramammary injection of dosages comprising a vehiclecontaining penicillin and polyvinylpyrrolidone.

2. The treatment of bovine mastitis and udder infection which comprisesperiodic intramammary injection of dosages comprising a vehiclecontaining from 100,000 to 1,000,000 units of penicillin andapproximately 1 gram of polyvinylpyrrolidone.

3. The treatment of bovine mastitis and udder infection which comprisesperiodic intramammary injection of dosages comprising a vehiclecontaining from 500,000

' to 1,000,000 units of penicillin and approximately 1 gram ofpolyvinylpyrrolidone.

4. The treatment of bovine mastitis and udder infection which comprisesperiodic intramammary injection of dosages comprising a vehiclecontaining from 500,000 to 1,000,000 units of penicillin andapproximately 1 to 2 grams of polyvinylpyrrolidone.

5. The treatment of bovine mastitis and udder infection which comprisesperiodic intramammary injection of dosages comprising a vehiclecontaining penicillin, dihydrostreptomycin and polyvinylpyrrolidone.

6. The treatment of bovine mastitis and udder infection which comprisesperiodic intramammary injection of dosages comprising a vehiclecontaining penicillin, dihydrostreptomycin and approximately 1 gram ofpolyvinylpyrrolidone.

7. The treatment of bovine mastitis and udder infec tion which comprisesperiodic intramammary injection of dosages comprising a vehiclecontaining from 100,000 to 1,000,000 units of penicillin, approximatelyA to 1 gram of dihydrostreptomycin and approximately 1 gram ofpolyvinylpyrrolidone.

8. The treatment of bovine mastitis and udder infection which comprisesperiodic intramammary injection of dosages comprising a vehiclecontaining penicillin, streptomycin and polyvinylpyrrolidone in theapproximate proportions of 1 gram of each of the dihydrostreptomycin andpolyvinylpyrrolidone to 1,000,000 units of penicillin.

References Cited in the file of this patent UNITED STATES PATENTS2,467,583 Cosar Apr. 19, 1949 2,728,704 Edds Dec. 27, 1955 2,745,785Bruce May 15, 1956 2,792,329 Woodard May 14, 1957 2,793,156 Souler May21, 1957 OTHER REFERENCES Milberg et al.: Evaluation ofPolyvinylpyrrolidone as a Retardant Agent for Penicillin," Antibioticsand Chemotherapy, August 1954, pp. 871-876. V

1. THE TREATMENT OF BOVINE MASTITIS AND UDDER INFECTION WHICH COMPRISESPERIODIC INTRAMAMMARY INJECTION OF DOSAGES COMPRISING A VEHICLECONTAINING PENICILLIN AND POLYVINYLPYRROLIDONE.